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Assessment and Management
Principles in Intellectual Disability
Psychiatric presentations in intellectual disability occur atypically
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PSYCH INSIGHTS
CONTENTS
Obsessive Compulsive 4
Disorder (OCD)
14Post Traumatic Stress
Disorder (PTSD)
24Inside the Mind of
Adult ADHD Specialist
30The Impact of Alcohol
on the Brain
40The Simplified Guide
to the Gut Brain Axis
References 49
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No reproduction permitted without written permission.
3
Psych Scene Hub
Obsessive Compulsive
Disorder (OCD)
A Primer on Neurobiology, Diagnosis and Treatment
The hallmark of obsessive-compulsive CLINICAL
disorder (OCD) is the presence of obsessions PRESENTATION
and compulsions. It has a bimodal incidence AND DIAGNOSIS
with peaks occurring in late childhood/early
adolescence and again in early adulthood (20-29). Obsessions
The lifetime prevalence of OCD is believed to be Persistent, unwanted, repetitive, intrusive
between 1% and 3%, and patients can experience thoughts, images and urges which are ego-
chronic or episodic OCD symptoms throughout dystonic and cause anxiety and distress
their lifetime. OCD is a time-consuming and
distressing mental state that has higher disability- Compulsions
adjusted years than Parkinson’s disease and
multiple sclerosis, combined making OCD one of Repetitive behaviours or mental acts performed in
the top 10 most disabling medical conditions. [1] response to an obsession to reduce the anxiety or
distress to prevent a feared consequence.
OCD is believed to diminish the quality of life of
the patient similar in extent to those individuals
with schizophrenia. [2]
OCD symptoms are time-consuming and
distressing and are often accompanied with strong
avoidance behaviours.
OCD is under-recognised, under-treated as well
as frequently mistreated. We summarise the key
diagnosis and treatment modalities in OCD based
on the latest guidelines. [3], [4]
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PSYCH INSIGHTS
Types of obsessions and compulsions
Screening Diagnosis
Recently validated screening tools include The diagnostic criteria and diagnostic interviewing
the Yale-Brown Obsessive-Compulsive Scale for OCD are covered previously.
(Y-BOCS), which has good reliability and is widely
used in clinical research.[5], [6] An OCD diagnosis is based on clinical
assessments of obsessive thoughts or compulsive
However, utilising the Y-BOCS screening tool behaviours that last more than one hour per day
requires adequately trained medical staff to and are not the result of a medical condition or
accurately assess the presence and severity of 64 substance abuse. Patients also do not have to
unique obsessions and compulsions. show both obsessive and compulsive traits to be
diagnosed as suffering from OCD.
There are other screening tools that, although not
as well validated, are still as reliable and sensitive. The Diagnostic and Statistical Manual of Mental
These include the obsessive-compulsive Disorders (5th edition) specifies OCD symptoms
inventory short version (OCI-SV), which only as clinically separate from delusions or persistent
takes 5 minutes to complete and has 18 items negative thoughts that may be associated with
that are scored based on the degree of distress other psychiatric disorders such as depression or
associated. generalised anxiety.
There is also, the Florida Obsessive-Compulsive The DSM-5 created a separate section called
Inventory, which has a 20-item checklist on a OCD and related disorders due to phenotypic,
5-choice scaling system. genetic, neuroimaging and treatment response
data suggesting OCD and related disorders are a
distinct entity.
5
Psych Scene Hub
OCD
The related disorders included are:
• Body Dysmorphic Disorder • Hoarding disorder • The ICD-11 consists of tic
disorders, hypochondriasis
• Hoarding Disorder • Substance/medication- and olfactory reference
syndrome.
• Trichotillomania induced OCD
• Skin picking disorder • OCD due to another
medical condition
NEUROBIOLOGY OF OCD
The cortico-striatal-thalamic-cortical loop (CSTC) is considered the critical brain circuit involved in
the phenomenology of OCD. The CSTC circuit plays an essential role in information processing.
According to Saxena et al., who proposed the model [7] –
OCD is mediated by an imbalance between the direct (excitatory, OFC-striatum-globus pallidus-
thalamus-cortical) and indirect (inhibitory, DLPFC-striatum-globus pallidus-subthalamic nucleus-
cortical) pathways within this circuit, which causes brain lock in the caudate nucleus and a mutual
hyperactivation between the OFC and thalamus.
The imbalance indicates that the ‘brake’ that would control repetition is faulty.
Functional neuroimaging studies have shown increased activation in the areas of basal ganglia
(predominantly head of caudate), anterior cingulate, and orbitofrontal cortex in OCD patients as compared
to healthy controls. [8], [9]
Overactivation of the cortico-striatal-thalamic-cortical loop is
associated with obsessions
OFC – ORBITOFRONTAL
CORTEX
S – STRIATUM
T – THALAMUS
Stahl, S. M. (2013). Stahl's essential
psychopharmacology: neuroscientific basis and
practical applications. Cambridge university press.
6 ©Psych Scene Pty Ltd 2018. All rights reserved.
PSYCH INSIGHTS
Neurotransmitter systems in OCD
1. Serotonergic system
2. Glutamate – primary driver of the CSTC circuit
3. Dopamine – the direct and indirect pathway mentioned earlier consists of D2 and D1 receptors
respectively, the imbalance of which affects the brake that controls repetition.
TREATMENT GUIDELINES
A recent clinical review attempted to outline the current guidelines on screening, diagnosis and treatment
of OCD. [3]
This evidence review of the literature initially compiled
792 unique articles that consisted of randomised-
controlled trials (RCTs), meta-analyses or systematic
reviews. Of these 792 articles, 27 were selected based
on the quality of evidence and their clinical importance.
DLPFC is part of the indirect inhibitory pathway of the
cortico-striatal-thalamic-cortical loop (CTSC)
DLPFC – DORSOLATERAL
PREFRONTAL CORTEX
S – STRIATUM
T – THALAMUS
Stahl, S. M. (2013). Stahl's essential
psychopharmacology: neuroscientific basis and
practical applications. Cambridge university press.
7
Psych Scene Hub
OCD
PSYCHOTHERAPY PHARMACOTHERAPY
Although a systematic review and meta-analysis SSRI’s
showed that cognitive behavioural therapy
(CBT) has been shown to be more effective than SSRI’s are considered the first line in the
selective serotonin reuptake inhibitors (SSRIs), in treatment of OCD.
clinical practice both SSRI’s and CBT are often
used together. [10] Trials have shown no difference between any
particular SSRI in treating OCD symptoms.
Both individual or group CBT are as effective
as each other in the treatment of OCD with the High dose SSRI’s have been shown to be more
most common psychotherapeutic approach being effective than lower doses. The medication and
exposure-response prevention CBT (ERP-CBT). target doses are:
• Fluoxetine – 80mg/day
Exposure-response prevention CBT is a structured • Fluvoxamine – 300 mg/day
form of psychotherapy whereby the patient is • Sertraline – 200 mg/day
exposed to situations that would provoke the • Paroxetine – 60 mg/day
obsessions and associated anxiety and distress • Citalopram – 40 mg/day
and then instruct the patient to resist the • Escitalopram – 40 mg /day
associated compulsions or avoidance behaviours. SSRI’s should be prescribed for at least 12 weeks
to determine responsiveness.
The psychological mechanisms underpinning this
technique are habituation and extinction. Approximately 25% of patients with refractory
OCD to SSRI’s may benefit from up to 28 weeks
• Habituation is the decline in response after treatment after initiation.
repeated exposure to a stimulus. SSRI’s should be prescribed for at least 6-12
months after response to prevent a relapse.
• Extinction refers to the cessation or reduction
Clomipramine
of behaviour when a reinforcer is taken away
or ceases. The tricyclic antidepressant, clomipramine, has
larger effect sizes for a response than SSRI’s.
Exposure-response prevention CBT is advised
to have a frequency and duration of 13 to 20 It can be started at 25 milligrams per day. A target
weekly sessions or 3 weeks of daily sessions. If dose of 250 milligrams per day is recommended.
necessary, additional sessions can then be offered
to the patient 3 to 6 months after the first session. However, patient tolerability is poor due to
significant anticholinergic side effects (dry mouth,
blurred vision, fatigue, tremor and hyperhidrosis).
Therefore, based on safety data, clomipramine
should instead be used as a second-line agent.
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PSYCH INSIGHTS
TREATMENT NEUROMODULATION
REFRACTORY OCD THERAPIES
Approximately 25% of all OCD patients will be Neurosurgery
classified as treatment-resistant: this is defined as
failing two different SSRI courses. Ablative neurosurgery involves producing
lesions in specific regions of the CSTC circuit.
Furthermore, 40-60% of all patients may be Neurosurgery is indicated in only severe cases
considered as responding positively to treatment of OCD. Approximately 60 percent of patients
but will have ongoing residual symptoms. improve 6-24 months post surgery.
Antipsychotics Key techniques for surgery are:
• anterior cingulotomy
Augmentation with antipsychotics is effective in • capsulotomy
30% of treatment-resistant patients. Haloperidol • subcaudate tractotomy
is an effective augmentation agent in OCD with • limbic leucotomy (combination of anterior
comorbid tics.
• Aripiprazole 5-10mg/day cingulotomy & capsulotomy)
• Risperidone 1-3mg/day
• Haloperidol 2.5-10mg/day Deep Brain Stimulation
• Olanzapine 5-10 mg /day
Involves targeting the anterior limb of the internal
NOVEL AGENTS capsule, nucleus accumbens, ventral caudate,
thalamus, subthalamic nucleus and ventral
Glutamatergic agents striatum. A metanalysis showed a 60 percent
response rate with DBS. [11]
• Memantine 10-20 mg/day
• Lamotrigine 100mg/day rTMS
• Topiramate 100-200mg/day
• N-Acetylcysteine 2400-3000 mg/day The regions associated with OCD are not usually
accessible by TMS. However, there is some
(Listen and read to Prof Berk’s talk on evidence of efficacy.
application of NAC in OCD and other disorders)
5 HT-3 Antagonists
• Ondansetron (2-4 mg BD) and
Granisetron (1mg BD)
Nutraceuticals
• Myoinositol
• 5HT
• Milk thistle
9
Psych Scene Hub
OCD
COMORBIDITIES IN OCD
Depression [12] Bipolar Disorder
• Depression is the most common comorbidity • In comorbid bipolar disorder, OCD can manifest
in OCD. We covered a case report on OCD and with increases in severity in depressive
depression and how augmentation strategies episodes but improvement during manic/
can treat both OCD and depression. hypomanic episodes.
• Depressive cognitions are ruminative and • Mood stabilisers or atypical antipsychotics are
have an ego-syntonic quality with thought considered the first choice of treatment.
content revolving around guilt, self-criticality,
self-doubt, nihilism, worthlessness and • If OCD persists despite treatment with a mood
hopelessness. stabiliser/atypical antipsychotic, then SSRI’s
can be used as an augmentation strategy.
• SSRI’s on their own may be associated with a
worsening of underlying bipolarity.
Anxiety Disorders [12] Schizophrenia/Psychosis
• Comorbid anxiety is associated with a poorer Individuals with schizophrenia have a significant
treatment outcome. incidence of OCD symptoms (25%). This
association may be related to:
• Anxious thoughts are related to real life
concerns and are not associated with • the prodromal phase of psychosis
compulsions.
• neuroleptic-induced OC symptoms (atypical
• SSRI’s are effective in the treatment of anxiety antipsychotic medications, e.g. clozapine,
and OCD. risperidone and olanzapine can increase OC
symptoms
• OCD occurring concurrently in psychosis
• Schizo-obsessive presentation [13]
SSRIs may be used in treating OCD comorbid with
schizophrenia.
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PSYCH INSIGHTS
Personality Disorder Tic Disorders
• Obsessive-compulsive personality disorder / • Presence of comorbid tics may predict a poor
Anankastic personality disorder is the most response to SSRI’s.
commonly associated personality disorder.
• Tic disorders show the best response
• Excessive preoccupation with perfectionism, to antipsychotics (haloperidol, pimozide,
orderliness, and rigid control. Stubbornness, risperidone and aripiprazole).
scrupulosity and over-conscientiousness are
key traits. • Adrenergic 2 agonists (clonidine and
guanfacine) are also evidence-based.
• Habit-reversal therapy (HRT) is a potential
first-line treatment option instead of or in
combination with pharmacotherapy.
11
Psych Scene Hub
OCD
SUMMARY ALGORITHM
Screen for OCD; if present, assess
severity and associated conditions
Mild to moderate OCD;
patient has good insight
Begin CBT with ERP component or
SSRI
Improvement within 12 wks? Minimal or none
Initiate SSRI
Yes
Taper CBT with ERP component with
monthly “booster” sessions for 3 to 6
months
Improvement in 8 to 12 wks?
Ye#
Minimal or none
1. Taper CBT with ERP component 1. Consider referral to specialist for
with monthly “booster” sessions for medication or behavioral
3 to 6 months management
2. Continue SSRI for 1 to 2 yrs. before a 2. Consider alternative diagnostic
gradual taper explanations for symptoms or
presence of additional comorbidities
3. Continue to regularly monitor for
symptom exacerbation
4. Consider restarting CBT with ERP
component during medication
tapering
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12 ©Psych Scene Pty Ltd 2018. All rights reserved.
PSYCH INSIGHTS
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13
Psych Scene Hub
Post Traumatic
Stress Disorder (PTSD)
A Primer on Neuropsychiatry and Treatment
Psychological trauma involves the witnessing of a traumatic or life-threatening event directly to your self
or to others. The individual is likely to experience intense fear, horror and helplessness, which can result
in a permanent or transient psychological wound characterized by physical, cognitive, emotional and
behavioural changes.
For most, the trauma is acute and transient and results in minimal functional impairment.
The psychological trauma can be classified into three clusters of symptoms. These include:
• Re-experience – Flashbacks, nightmares, and intrusive thoughts
• Hyper-arousal – Insomnia, agitation, irritability, impulsivity, and anger
• Avoidance – Numbing, withdrawal, confusion, dissociation, and depression
For some, however, the syndrome persists and this is termed post-traumatic stress disorder (PTSD).
A PTSD diagnosis was originally considered a normal response to an extreme situation however the
presence of symptoms for an extended period of time beyond one month is indicative of an abnormal
adaptation in the brain.
The prevalence of PTSD varies across countries. It occurs in 5-10% of the population and has a 2:1
female to male ratio. The gender bias may be a result of a combination of a greater propensity to lifetime
violence exposure and genetic vulnerability (variation in the ADCYAP1R1 (pituitary receptor) gene). [1]
In military populations the risk is more significant. For example 10 years after the Vietnam war, the
rates of current PTSD went up to 28% in those who had experienced combat exposure. Recent analysis
showed that 40 years after the end of the war, 11% of Vietnam veterans are experiencing PTSD
symptoms. [1]
In civilian population samples, the rates vary from 0.2%-3.8%. A number of factors such as social
supports, trauma type, and severity affect prevalence.
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PSYCH INSIGHTS
DIAGNOSTIC CRITERIA
The Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5) recognises several criteria
for a PTSD diagnosis. The PTSD criteria are as follows:
• Exposure to stressor • Alterations in arousal and reactivity
The individual was either directly or indirectly Disturbances to arousal and reactivity that
(witnessing, learning, or exposure to aversive began, or worsened, after the trauma are
details) exposed to trauma. characterised by aggression, self-destructive
or reckless behaviour, hyper-vigilance,
• Intrusion symptoms (one required) exaggerated startle response, and difficulty
concentrating or sleeping.
The trauma is persistently re-experienced via
recurrent memories, nightmares, flashbacks, • Duration
psychological distress, or physiological
reactivity to traumatic reminders. Criteria B-D must be present for at least one
month.
• Persistent avoidance (one required)
• Functional significance
Avoidance of trauma-related stressors:
recurrent trauma-related thoughts or Trauma-related symptoms must cause
environmental reminders such as people, psychological, social, or functional impairment.
activities, and places that act as visual
reminders. • Exclusion
• Negative alterations in cognition and Trauma-related symptoms cannot be attributed
to anything else such as medications or
mood (two required) substance abuse.
Inability to recall key features, persistent
(and often distorted) negative beliefs and However, trauma outcomes vary across
expectations about oneself or the world, individuals, and this appears to be dependent
persistent distorted blame of self or others, on genetic susceptibility factors, history of prior
persistent negative trauma-related emotions, psychological trauma, or an additional physical
markedly diminished interest in pre-traumatic injury at the time of the traumatic event such as
activities, feeling alienated from others and traumatic brain injury (TBI).
constricted affect (persistent inability to
experience positive emotions).
15
Psych Scene Hub
PTSD
NEUROBIOLOGY OF PTSD
The neurobiology of PTSD is complex and involves neuroendocrine, neurochemical and neuroanatomical
changes in neural networks.
Neuroendocrine Features Cortisol [1], [2]
The hypothalamic-pituitary-adrenal (HPA) In PTSD, there exists a dysregulation of
axis is the central coordinator of how humans glucocorticoid signalling underpinned by
respond to stress. The stress response starts in the heightened negative feedback sensitivity of the
hypothalamus where paraventricular neurons (PVN) HPA. This results in low cortisol levels and blunted
secrete corticotropin-releasing hormone (CRH). ACTH responses to CRH due to elevated levels of
CRH resulting in down-regulation of CRH receptors
This hormone stimulates the release of adrenocorti- on the anterior pituitary.
cotropin hormone (ACTH) from the anterior pituitary,
which in turn stimulates the release of glucocorticoids Two genes that are thought to be involved are
(e.g. cortisol) from the adrenal cortex. NR3C1 (encoding the glucocorticoid (GC) receptor)
and FKBP5 (role in immunoregulation and
Cortisol exerts a negative feedback control of regulating the amount of GC available to the GC
the HPA. Cortisol also reduces the noradrenergic receptor)
stress response.
Evidence suggests that low cortisol at the time of
Sustained cortisol exposure has an adverse effect on exposure to trauma may predict the development
the brain, particularly hippocampal neurons, resulting of PTSD and that hypocortisolaemia may be a
in impaired neurogenesis and neuroplasticity. risk factor for the development of PTSD. This may
explain why high dose hydrocortisone IV after
The hippocampus and pre-frontal cortex have an trauma may prevent the development of PTSD. [3]
inhibitory effect on HPA while the amygdala and
aminergic brain stem neurons stimulate the HPA.
HPA AXIS in PTSD
Stress releases CRH from the hypothalamus which in turn In PTSD there is dysregulation of glucocorticoid
releases ACTH from the anterior pituitary. ACTH stimulates signalling with sensitised negative feedback of the
release of cortisol from the adrenal cortex. Cortisol exerts a HPA axis resulting in increased CRH and blunted
negative feedback control of the HPA axis. ACTH responses to CRH which results in reduced
cortisol secretion.
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PSYCH INSIGHTS
Neurochemical Features: [1], [2]
Serotonin
• Decreased serotonin transmission in the dorsal and median raphe is related to hyper-vigilance,
increased aggression, impulsivity as well as the enhanced formation and resilience of intrusive
memories providing a role for SSRI’s in the treatment of PTSD.
• 3,4-Methylenedioxymethamphetamine (MDMA) is being studied in the treatment of PTSD as it
increases serotonin levels. [4]
Noradrenaline
• Noradrenaline (NA) mediates the stress response through central and peripheral mechanisms.
• In PTSD there is increased noradrenaline transmission in networks that connect the locus coeruleus
to the amygdala and hypothalamus (the noradrenergic feed-forward circuit).
• The enhanced NA release is associated with increased fear conditioning and enhanced encoding of
emotional memories with increased arousal and vigilance.
• For example, yohimbine, a 2-adrenergic receptor antagonist, increases NA release inducing
flashbacks and increased autonomic responses in patients with PTSD.
• Along the same lines, propranolol administration ( 2-adrenergic antagonist) after exposure to trauma
can reduce PTSD symptom severity and reactivity to trauma cues.
• Noradrenergic feedforward circuit in PTSD
Noradrenergic Feed Forward Circuit
The amygdala & hypothalamus are connected with the LC where Corticotrophin releasing
hormone (CRH) and noradrenaline (NA) interact to increase fear conditioning, encoding of
emotional memories and enhance arousal and vigilance. (Sherin and Nemeroff, 2011)
17
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PTSD
Dopamine Neuro-anatomic Features
• Dopamine is implicated in the regulation of Using structural brain imaging, circuits that are
fear conditioning and anxiety. In individuals associated with adaptation to stress and fear
with PTSD, there is a genetic component conditioning have been shown to be structurally
associated with dopamine metabolism that altered in patients with PTSD.
governs whether an individual develops PTSD
as well as what symptoms they may display. Hippocampus
Others • Reduced hippocampal volume is a hallmark
feature of PTSD. The hippocampus plays
• Glutamate (excitatory) release via the NMDA an important role in fear extinction and
receptors involved in synaptic plasticity, conditioning, stress responses and declarative
learning and memory. memory.
• GABA (inhibitory) release mediating anti- • Stress via enhanced cortisol secretion is
anxiety effects. known to impair hippocampal neurogenesis
and damage hippocampal neurons which may
• Proinflammatory cytokines involved in explain the smaller hippocampal sizes found in
neuroinflammation patients with PTSD. [5]
• Endocannabinoids (anandamide, • A recent study, however, postulates that
2-arachidonoylglycerol) mediate memory smaller hippocampal (left) volume is a risk
consolidation via CB1 receptors. factor in the persistence of PTSD as opposed
to a result of PTSD. [6]
• Neurosteroids (allopregnanolone) have an
inhibitory effect on glucocorticoid and NA
signalling.
• Neuropeptides (neuropeptide Y, enkephalin
endorphins, BDNF and DHEA)
18 ©Psych Scene Pty Ltd 2018. All rights reserved.
PSYCH INSIGHTS
Amygdala Medial prefrontal cortex
(PFC)
• The amygdala plays a crucial role in emotional
processing and the acquisition of fear • The medial PFC (contains the anterior
responses. cingulate cortex (ACC)) is connected to the
amygdala and has inhibitory control over its
• The amygdala remembers a stressful response stress responses and emotional reactivity to
by increasing glutamate transmission which different stimuli.
consolidates the traumatic memory via NMDA
receptor activity. Upon future exposure to • The medial prefrontal cortex mediates fear
a traumatic reminder, a fear response is extinction through inhibition of acquired fear
activated. responses.
• Structural MRI analysis has revealed • Decreased frontal cortex and ACC volumes are
pathological damage to the amygdala, which found in patients with PTSD.
was associated with a hyper-responsive
reaction to subliminally threatening cues. [7] • In PTSD, a decreased PFC volume correlates
with symptom severity due to decreased
• Individuals with PTSD may show hypo- and inhibitory control over the amygdalar stress
hyper-activity within distinct regions of the response.
amygdala sub-nuclei.
• Downstream from the amygdala is the
Periaqueductal gray (PAG) which is an
important site mediating fear responses such
as flight/ fight or freeze responses.
AFFECT OF FEAR RE-EXPERIENCING OF
TRAUMATIC MEMORIES
- - .+*).
FEAR RE EXPERIENCING
MEMORIES
ACC: Anterior cingulate cortex (part of the medial prefrontal cortex) $"#/>!'$"#/ *- !- 5
VMPFC: Ventromedial prefrontal cortex
PAG: Periaqueductal gray
Stahl, S. M. (2013). Stahl's essential psychopharmacology: neuroscientific basis and practical applications.
Cambridge university press.
19
Psych Scene Hub
PTSD
PTSD PHENOTYPES INTEGRATED MODEL
OF PTSD
The dynamic interaction between the medial
prefrontal cortex and the amygdala creates two Three key brain networks have been identified as
distinct phenotypes in PTSD patients. [1] central to higher cognitive function:
EMOTIONAL EMOTIONAL • Salience network (detection of salient internal
UNDERMODULATION OVERMODULATION and external stimuli)
• Diminished prefrontal • Increased prefrontal • Default mode network (emotional regulation,
inhibition of limbic inhibition of limbic social cognition, future thinking and
regions system autobiographical memory)
• Heightened emotional • Emotional detachment • Central executive network (cognitive function)
and autonomic responses with emotional numbing,
depersonalisation and The anterior insula acts as a switch between
• Decreased VMPFC derealisation engaging the executive netwrok and disengaging
and ACC activation the default mode network allowing for better
with increased • Increased medial functioning of higher cognitive processes.
amygdala activity prefrontal cortex and
ACC activity with Abnormalities in these three areas are associated
VMPFC: Ventromedial prefrontal cortex decreased amygdala with specific clinical symptoms in PTSD as shown
ACC: Anterior cingulate cortex activation in the diagram below. [1]
20 ©Psych Scene Pty Ltd 2018. All rights reserved.
PSYCH INSIGHTS
TREATMENT
PTSD develops through a combination of psychological and biological mechanisms.
Treatment modalities aim to address the various psychological and biological components.
In some cases, a combination of medication and psychotherapy is required.
Development of PTSD
Trauma
Increased . ) *! Low cortisol levels due to
noradrenergic activity )*- - ) -"$ $)#$ $/$*) HPA dysregulation
Enhanced consolidation
of traumatic memories
Increase in fear Amygdala activation
conditioning results in exaggerated fear
Adverse stimuli linked response to traumatic
with non-specific neutral memories
stimuli which become )"*$)" /$1 /$*) 4
triggers . '$ )/ /-$"" -.
Difficult to achieve fear PTSD
extinction, habituation
and desensitisation
Two important concepts in PTSD treatment are:
• Kindling – Process through which increasingly low severity stimuli can activate negative responses
over time
• Sensitisation – When people are repeatedly exposed to negative stimuli, progressively greater
responses develop over time.
Treatment aims to achieve fear extinction, desensitisation and intervene in the kindling process.
21
Psych Scene Hub
PTSD
Psychotherapy
Psychotherapy is considered a first-line therapy and can be divided into trauma-focused, and non-
trauma focused psychotherapy.
Trauma-focused CBT has been most extensively studied and shown to be effective.
Prolonged exposure therapy and cognitive processing therapy are two types of trauma-focused CBT.
They are based on the principles of extinction learning, habituation and desensitisation.
Trauma-focused therapy Non-trauma-focused therapy
• Prolonged Exposure therapy: Progressive • Supportive therapy
exposure to the trauma narrative and trigger • Non-directive counselling
settings. • Mindfulness and patient centred therapy
• Interpersonal therapy
• Cognitive-processing therapy: Involves writing • Yoga and mindfulness training
a trauma narrative and repeatedly reading it as
a means to expose the trauma memory. It also “Patients with a history of interpersonal
addresses shame, guilt or feelings of mistrust. violence, early life trauma or those with
In this sense, culturally-adapted CBT has also a complex presentation of PTSD that
been useful as this technique offers a more includes emotional detachment might
specific paradigm to treat PTSD. be better treated with phase-oriented
approaches.
• Narrative exposure therapy: A short-term
approach that involves the chronological Phase oriented approaches involve
cataloguing of their life and an in-depth skills training, mood regulation and
detailing of all traumatic events. This therapy grounding, identifying attachment
was developed for the survivors of the schemas an developing competence in
Pinochet regime in Chile and has proven to be social interactions.
very useful in overcoming trauma.
Once these skills have been developed,
• Eye Movement Desensitization and the patient can then participate in
Reprocessing (EMDR) modified exposure-based therapy
focusing on emotional stability and
EMDR is a: negative personal schemas.”
“A therapy aiming to process
distressing memories by having the – Yehuda et al., 2015
patient recall distressing images
while receiving one of several types This type of PTSD is often called complex trauma
of bilateral sensory input, including disorder or complex PTSD. Prof. Kulkarni talks
side-side eye movements” about trauma and complex trauma disorder in
– Yehuda et al., 2015 women. A/Prof. Sathya Rao discusses the overlap
of complex trauma disorder with Borderline
Personality Disorder.
22 ©Psych Scene Pty Ltd 2018. All rights reserved.
PSYCH INSIGHTS
Pharmacotherapy [1]
“Current evidence favours selective serotonin reuptake inhibitors as the class with the
most evidence supporting their use as first-line psychopharmacological treatment options.”
– Yehuda et al., 2015
A recent systematic review, commissioned by topiramate, and tiagabine can be prescribed
the WHO, showed that although some SSRIs are as monotherapy or as an adjunctive treatment
statistically superior to placebo, the effect size is for their GABA potentiating and anti-kindling
small. [8] effect.
When reviewing methodologically robust • Anti-adrenergic drugs ( 1, 2 and
pharmacotherapy trials, Hoskins and colleagues
found that only fluoxetine, paroxetine, and receptors) – Examples include prazosin,
venlafaxine have statistically significant data on guanfacine, alfuzosin, doxazosin, propranolol
reducing PTSD symptoms compared to placebo. and clonidine, which have been used as
a treatment strategy for PTSD-related
Many other interventions are currently used off- nightmares.
label for the treatment of PTSD, and these drugs
are based on the neurobiology of PTSD symptoms. • Other experimental treatment –
These include:
D-cycloserine (glycine receptor agonist),
• Antidepressants – In addition to paroxetine endocannabinoids, neuropeptides (NPY
antagonists, cholecystokinin antagonists,
and sertraline, phenelzine, imipramine, substance P antagonist, and nalmefene
desipramine, amitriptyline, fluoxetine, (endogenous opioid antagonist)), ketamine,
brofaromine, bupropion and mirtazapine are mifepristone and hydrocortisone
the favoured first-line treatment option.
Clinical Pearl:
• Antipsychotics – Dopaminergic blockade
PTSD is co-morbid unless proven otherwise.
with risperidone, olanzapine, and quetiapine, Diagnostic overshadowing, whereby symptoms
however, cardiovascular and metabolic side- are attributed only to trauma, may result in mis-
effects mean that extra caution is advised diagnosis and inadequate treatment.
when prescribing these agents.
It is therefore crucial for clinicians to diagnose and
• Anticonvulsants – Valproate, carbamazepine, treat any other co-morbid conditions.
phenytoin, phenobarbital, lamotrigine,
CONCLUSION
Traumatic stress has a broad range of effects on the function and structure of discrete regions of the
brain that have critical roles in emotion, memory, and reactivity.
PTSD is best understood as a heterogenous disorder with different phenotypes based on the brain
circuits involved. Co-morbidity is high and clinicians should always be vigilant for the presence of other
psychiatric disorders.
23
Psych Scene Hub
Inside the Mind
of Adult ADHD
Specialist
Interview with Dr Mahendra Perera
HI DR PERERA, THANK YOU FOR TALKING TO PSYCHSCENE
HUB. CAN YOU GIVE OUR HUBSTERS A BRIEF BACKGROUND
ABOUT YOURSELF?
Thank you Sanil. I am a member of the Royal College of Psychiatrists and a Fellow of the Australasian
College. I also hold a Fellowship of the Chapter of Addiction Medicine in the College of Physicians. I
completed my MBBS in Sri Lanka and have been in Australia since 1992. I am now doing locum work in
different parts of Australia after being in private practice for several years. I am also an Honorary Senior
Fellow of the Department of Psychiatry, University of Melbourne.
Dr. Mahendra Perera
MBBS, PhD, MD (Psych), MRCPsych, FRANZCP, FAChAM
Dr Mahendra Perera, is a Member of the Royal College of Psychiatrists and a Fellow of the
Australasian College. He also holds a Fellowship of the Chapter of Addiction Medicine in
the College of Physicians.
His MBBS is from Sri Lanka and has been in Australia since 1992. He is now doing locum
work in different parts of Australia. He has experience in managing adults with Attention
Deficit Hyperactivity Disorder (ADHD) He is also in Near Death Experiences. He is a
biologically oriented psychiatrist, a researcher with publications in peer-reviewed journals,
Principal Editor of “Making Sense of Near Death Experiences: a handbook for clinicians”
and an Honorary Senior Fellow of the Department of Psychiatry, University of Melbourne.
24 ©Psych Scene Pty Ltd 2018. All rights reserved.
PSYCH INSIGHTS
CAN YOU GIVE OUR READERS WHY IS ADULT ADHD
A BRIEF IDEA OF YOUR SO IMPORTANT TO
EXPERIENCES IN TREATING RECOGNISE IN CLINICAL
PATIENTS WITH ADULT ADHD? PRACTICE?
Sanil, I would like to thank you for asking me to ADHD is a neurodevelopmental disorder that
talk about a topic which I am very interested in. begins in childhood and according to most of the
Before going on to my experiences, I think it’s best current literature about 50% remain symptomatic
to briefly outline how I got interested in the field. even in adulthood.
Since I worked in addiction psychiatry and then
did some child psychiatry work in the early 1990s, The problem is that the hyperactivity may not
I must say the penny dropped, regarding ADHD. be present in adults, but they have various other
Subsequently, as an adult general psychiatrist, I problems stemming from the core illness. There
think the first patient I diagnosed with ADHD had are some who believe that even if diagnosed in
various dependencies both alcohol and opioids childhood by the time they are adults the disorder
due to a chronic pain syndrome. I treated her disappears.
albeit with some trepidation, with stimulants. The
one redeeming feature was that the stimulants If on the other hand, they were not diagnosed in
were never abused. They were always used in the childhood, then, there is a bigger problem because
manner prescribed or less. those adults who for whatever reason got through
their childhood without a diagnosis continue to
Since then the number of people I saw with ADHD have problems or have greater problems as an
gradually increased until I stopped private practice adult. The condition when dealt with appropriately,
a couple of years ago when I had almost 80% of as I have mentioned earlier, is rewarding for
my practice with ADHD patients. the practitioner but much more so for the adult
sufferer.
I think treating people with the condition is very
rewarding but also demanding. You need to
separate the wheat from the chaff (otherwise there
are those who will approach you for stimulants) as
well as strictly adhere to the rules and regulations
of the state in which you practice as well as our
licensing requirements.
Once you set up your practice in a carefully
considered manner, it is less likely to come across
those who are seeking substances for hedonistic
purposes. The difficulty, however, is that patients
do not read a textbook and may have comorbid
conditions which need to be dealt with. The
most problematic of these being substance use
disorders.
25
Psych Scene Hub WHAT ARE THE
CORE FEATURES
Adult ADHD Specialist THAT ONE SHOULD
FOCUS ON IN
ADULT ADHD IS DIAGNOSIS?
CONSIDERED A
CONTROVERSIAL ADHD is diagnosed by hyperactivity,
DIAGNOSIS BY SOME. inattentiveness and impulsivity. These need to
WHAT IS YOUR VIEW be present or have been demonstrably present
ON THE DIAGNOSIS? in childhood. The DSM 5 has subsumed
impulsivity under hyperactivity.
In answer to part one of your question, there
will always be the naysayers of any illness or However, when dealing with adults, the
condition. Secondly and I hypothesise here that impulsivity and inattentiveness are more
it could be a lack of knowledge or information prominent than hyperactivity per se. The
regarding the condition. hyperactivity itself is characterised by a sense
of restlessness e.g. inability to sit for a long
Another reason could be that since more and period of time or have difficulty staying through
more people are coming out of the woodwork a lecture. Since the symptoms of ADHD have
with a presumptive diagnosis of ADHD, some been well noted in the DSM and on many other
may be of the view that colleagues are over websites I shall not detail these here.
diagnosing the condition or indeed to use the
cliche to someone with a hammer everything
is a nail. This need not be controversial at
all as the research clearly bears out that
the condition persists into adulthood and
prevalence rates have been well documented.
However, as with the other so-called functional
diagnoses, we make in Psychiatry, we do not
have clearly demonstrable pathological or
biochemical markers.
My view is that it exists, it needs to be
properly managed, and we need to educate
our colleagues as well as the public that it is
a disorder like any other condition such as
depression, OCD et cetera. Of course, each
psychiatrist may not wish to treat (especially)
the more challenging clients with ADHD. Each
of us does have a subspecialty niche. However,
that does not negate the fact that ADHD exists
in the adult.
26 ©Psych Scene Pty Ltd 2018. All rights reserved.
PSYCH INSIGHTS
WHAT ARE THE COMMON WHAT ARE THE KEY
CLINICAL PRESENTATIONS FEATURES IN THE
OF ADHD AND WHAT DIAGNOSTIC ASSESSMENT?
INDICATORS SHOULD
RAISE OUR SUSPICION? Once more we need to suspect a condition,
without which we would not be likely to look
This gets down to the core business of a clinician. for it. For me as a practising clinician, the key
There are several calling cards, and I shall briefly feature is the narrative offered by the individual
outline them here. The first – they have been and collateral history to ascertain the veracity of
diagnosed by a paediatrician and now as an adult the story. Personally, I would not diagnose ADHD
would like to continue with treatment OR the in the absence of childhood history suggestive of
paediatrician is looking for a psychiatrist to refer the condition. This information can be obtained
them on to for continuing therapy. I have received in many ways. Other than the individual account,
several such requests from my paediatrician I find that the school reports at least the ones
colleagues. There are others who have had I have seen are usually indicative. Comments
lifelong problems and either through friends or such as. “could do better if he only tried” is
self-reading would suspect they have ADHD and a constant theme. Collateral information from
request an assessment. parents or significant others is the another source
of information.
One caveat here is that the child with ADHD who
did not have any other difficulties may as an adult I tend to use a couple of questionnaires. I use
develop other physical or psychological problems the World Health Organisation (WHO) Adult ADHD
and hence re-evaluating or clarifying our role in Self-Report Scale (ASRSv1.1), which is an 18
the management is important. item questionnaire and is available freely on the
web. This is a self-administered questionnaire. I
One of the common features seen in the hitherto have been using the DSM items which have been
undiagnosed patient is that they may present as typed onto a Word document, and I use it as an
what I would loosely call a treatment resistant interviewer-administered questionnaire writing
depression or anxiety state which may well be my comments. DIVA is another questionnaire,
due to underlying ADHD. Impulsive behaviours and that is useful. There are many other
(above and beyond normal or societal bounds) and questionnaires, and it is useful for the clinician
substance use disorders may be due to underlying to become familiar with one or two to be able to
ADHD. More recently people have even thought of quantify the assessment.
ADHD underpinning some personality disorders.
There are various biological investigations.
It is always good to suspect ADHD as a probable However, as far as I’m aware none of them is
diagnosis amongst the other psychological specific for ADHD although EEG’s, scanning
diagnoses where it could be relevant. The axiom techniques have demonstrated statistically
here is that if we do not suspect we are not likely significant differences in those with ADHD
to diagnose. compared with those who do not have it.
Although I have not used it personally, a
commercially available tool is the Global Mind
Screen. This is a broad instrument which the
patient completes and offers a profile for probable
diagnoses including ADHD.
27
Psych Scene Hub
Adult ADHD Specialist
WHAT ARE THE KEY CAN YOU GIVE US A BRIEF
STEPS IN MANAGEMENT? OVERVIEW OF MEDICATIONS?
For me, the most important thing is to arrive at a Stimulants have been the cornerstone of
firm diagnosis and also assess for any co-morbid medication management. One of the very early
conditions. I would then explain my view to the studies dates back to 1930s when Benzedrine
individual patient and preferably a significant other was used. Currently, the two stimulants in vogue
due to the contentious nature of the condition. I are dexamphetamine and methylphenidate. For
would discuss management options. They are, both of these substances, the slow-release or
learning behavioural techniques, medication long-acting versions are available in Australia.
(stimulant and non-stimulant) and advocating However, there are certain restrictions regarding
for the patient if they are facing difficulties. I pharmaceutical benefits scheme (PBS) subsidies
always make it manifestly clear that ADHD is not for the long-acting medicine.
an excuse for bad behaviour. e.g. I would write
a letter on behalf of a student who was having I have listed some medicines that are used in
difficulty with handing in an assignment on time. ADHD. I think it is important the clinician become
Once more I make it very clear that once they are familiar with the medicines they are using and
adequately treated, they should have no excuse also be aware of cost and availability.
for further delay.
Stimulant
• Dexamphetamine 5 mg tablets (immediate
release- duration of action ~ 4hrs)
• Lisdexamfetamine (Vyvanse) 30, 50 and 70mg
capsules
• Methylphenidate 10 mg tablets
• Ritalin LA 10, 20, 30, 40 and 60 mg (PBS
restrictions apply)
• Concerta 18,27,36 and 54 mg (PBS
restrictions apply)
• Has been used although not product licensed
for ADHD [Modafanil (Provigil) 100 and
200mg] – No PBS subsidy for ADHD
Non-Stimulant
• Atomoxetine (Strattera) 10, 18, 25, 40, 60, 80
and 100 mg (PBS restrictions apply)
• Clonidine – has been used especially with
children – I have not personally used
• Guanfacine – Used in ADHD but I do not have
any further information
• Bupropion – mainly in the states available here
as Zyban for smoking cessation.
• Since sleep is a problem for some, they could
either use a smaller dose of a stimulant if they
are on one or melatonin 2 – 4 mg.
28 ©Psych Scene Pty Ltd 2018. All rights reserved.
PSYCH INSIGHTS
HOW DOES ONE CHOOSE ANY FINAL WORDS?
SPECIFIC STIMULANTS OR
NON-STIMULANTS? Although I have dealt with medication and the
diagnosis it is only briefly that I have mentioned
I would say this is an art as well as a science about behavioural techniques that could be used
and the prescriber/clinician needs to be aware to help these people. We are aware of neuronal
of this and be able to individualise the drug plasticity, and it is important that an individual
treatment regime. with the condition be aware that medicine is
only part of the answer if they choose to use the
For medical practitioners, these are vital medicines. There are many behavioural methods
questions which we need to grapple with on a that will also help and need to be applied
regular basis. If a patient has psychosis or is concurrently with medication.
substance dependent I would be reluctant to
use stimulants (but would not exclude such use Make sure that your permits are
if essential or necessary). up to date and prescribing is
within the guidelines.
In a straightforward situation, I will discuss the
pros and cons of medicines in general and There are many who would say that ADHD is a
offer them a choice of dexamphetamine or new diagnosis or a condition that has suddenly
methylphenidate because, for me, either of the erupted in the 20th and 21st centuries. Actually,
stimulants is much of a muchness. there are records of similar conditions been
described over hundreds of years. Certainly, the
A key principle for me is the condition does give an evolutionary advantage,
go low go slow approach to and since the gene pool does not turn over that
medication. fast, it is likely that the condition existed for
many centuries or millennia.
If they do have other comorbid conditions
that too would need appropriate medication The question of it being brought to light more
management. My recommendation is; always recently could be looked at in many different
begin with the straightforward patients with ways. The social and cultural pressure to
ADHD, get comfortable with prescribing achieve and especially in an academic sense
medication and then go on to more complex maybe one reason, another reason is the
situations. increase of environmental pollutants could
be contributing to the unmasking of certain
A peer review group and/or collaboration characteristics (epigenetic phenomena).
with the experienced clinician is helpful and Furthermore, the availability of knowledge freely
necessary. Even those of us who regularly do on the Internet may be another reason people
this work consult with our colleagues as and are becoming more aware of the condition and
when necessary. reaching out for help.
I do not have one answer to this, but I do
realise that ADHD is a condition that we need
to recognise and manage and when properly
approached is rewarding to both the clinician
and most importantly to the patient.
29
Psych Scene Hub
The Impact of
Alcohol on The Brain
Neurobiology of Dependence and Alcohol Related Brain Damage
Alcohol dependence, or alcoholism, is a chronic and severe condition that the WHO estimates to
affect 140 million individuals globally. The WHO classifies alcoholism as the 5th leading risk factor for
premature death and disability with between 10 to 20% of all males and 5 to 10% of all females being
diagnosed with alcohol dependency. [1]
In Australia, the total societal costs due to alcohol-related issues in 2010 were estimated to be
$14.352b. (Australian Government)
ETIOPATHOGENESIS Alcohol (ethanol) is liposoluble and can cross the
OF ALCOHOL blood-brain barrier where it has been shown to
DEPENDENCE interact directly, and indirectly, with a wide range
of neurotransmitters and hormones such as
The etiopathogenesis of alcoholism involves -aminobutyric acid (GABA), glutamate, dopamine,
a complex interplay between biological, opioids, epinephrine, norepinephrine, serotonin,
psychological and socio-environmental factors. acetylcholine, cannabinoids, corticotropin-
However, one of the strongest predictors is the releasing factor (CRF), and neuropeptide Y.
genetic disposition of an individual, with heritability
estimated to range between 50% and 64% of Alcohol dependence is characterised by deficits
cases.[2] in the physiological dysregulation of
motivation and reward systems, such as those
Variation in genes encoding enzymes involved in the limbic system, hippocampus, amygdala,
in the metabolism of alcohol dehydrogenase or caudate nucleus, frontal lobe and nucleus
aldehyde dehydrogenase has been shown to accumbens.
influence the risk of alcohol dependence. [3]
You can read more about the neurobiological
Young males who have experienced a traumatic basis of addiction in a previous post we covered.
event can develop low levels of MAO-A It covers the process of the progression from habit
expression (an enzyme that breaks down to compulsion.
serotonin), and this decrease in MAO-A levels
correlates with an increase in antisocial behaviour, The dysfunction of these systems is responsible
which is a risk factor for alcohol dependence. for acute alcohol intoxication, alcohol dependence,
and withdrawal syndrome.
30 ©Psych Scene Pty Ltd 2018. All rights reserved.
PSYCH INSIGHTS
NEUROBIOLOGY OF ALCOHOL DEPENDENCE
Alcohol has both positive and negative reinforcing actions on the brain.
Dopamine
The positive reinforcing action of alcohol comes from the activation of the dopaminergic reward
pathway in the limbic system. Dopamine is a neuromodulating compound that is released in the
ventral tegmental area (VTA) and projects to the nucleus accumbens (NA) where it is acutely
involved in motivation and reinforcement behaviours.
The Mesolimbic Pathway
Dopamine is the major neurotransmitter involved as
part of the mesolimbic system projecting from the Ventral
tegmental area (VTA) to the Nucleus accumbens (NA)
Studies have shown that there is a dose-response relationship between alcohol intake and dopamine
release.[4], [5]
This ethanol-induced dopamine release has been shown to be directly and indirectly promoted through
alcohol’s interaction with GABAergic neurons and opioid receptors in the nucleus accumbens. [6], [7], [8]
31
Psych Scene Hub
Impact of Alcohol
GABA: Glutamate: [10]
GABA is the brain’s major inhibitory Glutamate is the brain’s major excitatory
neurotransmitter. Alcohol acts presynaptically at neurotransmitter system. Alcohol reduces
the GABA neuron increasing GABA release and glutamate levels in the nucleus accumbens
postsynaptically enhancing GABA receptor action. and suppresses glutamate-mediated signal
transmission in the central nucleus of the
Baclofen, a GABA-B agonist, has shown to amygdala.
be very effective in the treatment of alcohol
dependence, and, in particular, extremely Alcohol alters NMDA and metabotropic MGlu5
efficacious in effortlessly reducing the motivation receptors thus interfering with glutamate
to drink. [9] transmission.
Acamprosate used in the treatment of alcohol
dependence has demonstrated that its mechanism
of action is through its inhibition of the NMDA
receptor.
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Alcohol reduces glutamate excitotoxicity (VTA) ; enhances GABA
inhibitory activity (VTA) and enhances dopamine release from the VTA
to NA by disinhibiting GABA via endogenous opioids. The release of
dopamine mediates alcohol’s pleasurable and reinforcing actions
32 ©Psych Scene Pty Ltd 2018. All rights reserved.
PSYCH INSIGHTS
Serotonin: [10] Acetaldehyde: [10]
There is evidence of a link between serotonin The primary breakdown product of ethanol is
deficiency, impulsivity and drinking behaviour acetaldehyde, which is produced through a series
which may explain the role of SSRI’s in of oxidative metabolic reactions. [12]
suppressing alcohol reinforced behaviour in some
alcohol-dependent patients. Acetaldehyde is a highly reactive compound that
reacts with several catecholamines (i.e. dopamine
On the other hand, SSRI’s are associated with and serotonin) in the brain.
new-onset alcohol dependence in some patients.
The differential effects highlight the presence of These reactions produce psychoactive alkaloids
different subtypes in alcohol dependence. such as salsolinol and tetrahydropapaveroline.
Opioid Systems: [10] These alkaloid compounds have been suggested
to be responsible for the physiological effects
Opioid systems involving endogenous opioids of alcohol as well as the manifestation of the
(endorphins, enkephalins and dynorphins) behavioural aspects of alcohol-related disorders.
influence drinking behaviour via interaction with
the mesolimbic system. Disulfiram is is a drug that inhibits the
enzyme aldehyde dehydrogenase and is used
Naltrexone is an opiate-receptor antagonist in the treatment of alcohol dependence. The
and has been shown to limit cravings by reducing accumulation of acetaldehyde is known to
the positive reinforcement effect of alcohol cause unpleasant side effects such as vomiting,
consumption. headaches, and anxiety after the consumption of
alcohol.
Moreover, naltrexone has been shown to reduce
alcohol priming (i.e. increased desire to drink), Disulfiram administration helps patients learn
which may reduce the likelihood of heavy drinking. non-drinking behaviours and the ability to exercise
self-control. In fact, most individuals cease alcohol
[11] use after the administration of disulfiram due to
the strong expectancy of negative consequences.
Other systems: [10]
• Norepinephrine
• Orexin
• Vasopressin
• Neuropeptide S and Y
• Corticotrophin Releasing Factor (CRF)
33
Psych Scene Hub
Impact of Alcohol
MECHANISMS OF ALCOHOL RELATED BRAIN
INVOLVEMENT [3]
Ethanol-specific Thiamine Liver dysfunction
effects deficiency
Elevated ammonia
• Toxic metabolites of ethanol Thiamine deficiency leads to Affects cerebral blood flow and
such as acetaldehyde and low levels of active thiamine astrocytic function
fatty acid ethyl esters can (thiamine pyrophosphate) in
disorder phospholipids, the brain which impairs several Elevated manganese
interrupt mitochondrial biochemical pathways in the Affects the dopaminergic
function, and induce brain: system, enhances oxidative
neuronal damage. stress, and induces neurotoxicity
Carbohydrate metabolism
• Oxidative stress via the For energy production Synergistic effects
generation of reactive oxygen
species (such as nitric Lipid metabolism Neuroinflammation (learn more
oxide and lipid peroxidation For the production and about neuroinflammation in the
products), that accumulate maintenance of myelin other article on the Hub).
and cause DNA damage,
inhibition of gene expression, Amino acid metabolism
and neuronal death For the production of GABA and
glutamate
• Reduction in Brain-Derived
Neurotrophic Factor (BDNF)
a neurotrophin necessary for
neuronal survival, growth,
and differentiation.
• Excitotoxic activity during
alcohol withdrawal
mediated via dysregulation
of glutamate release and
uptake, and stimulation of
NMDA receptors
34 ©Psych Scene Pty Ltd 2018. All rights reserved.
PSYCH INSIGHTS
ALCOHOL RELATED BRAIN INVOLVEMENT
The following are key neurofunctional abnormalities with key areas of the brain involved. [3], ,[13] [14]
• Executive function, impaired judgement, • Visuospatial abilities
impulsivity, blunted affect, distractibility, Corpus callosum
reduced motivation, and disinhibition
Frontal lobes • Upper and lower limb control
• Memory dysfunction Corpus callosum and cerebellum
Mammillary bodies, hippocampus, thalamus, • Oculomotor control
hypothalamus and caudate nucleus
Pons and cerebellum
Brain Areas Affected by Alcohol
35
Psych Scene Hub
Impact of Alcohol
WERNICKE-KORSAKOFF’S SYNDROME (WKS)
Wernicke’s Encephalopathy (WE)
Wernicke’s encephalopathy is an acute, yet Clinical Features:
potentially reversible, neuropsychiatric disorder
caused by a deficiency (or depletion) in thiamine Triad consists of:
(thiamine pyrophosphate) caused by chronic 1. Oculomotor abnormalities
alcohol use. Other causes include gastric bypass
surgery, gastric and colon cancer, hyperemesis Lateral rectus palsy, nystagmus,
gravidarum, long-term parenteral feeding, and ophthalmoplegia
poor nutrition. 2. Cerebellar dysfunction
Ataxia
Genetic susceptibility linked to thiamine 3. Altered mental state
transporter genes may be involved in the Confusion
development of WKS in vulnerable patients.
Clinical Pearl – Only 20% of patients may show
Wernicke’s encephalopathy is a medical the full triad in clinical practice.
emergency. Untreated, it leads to death in up to
20% of cases. The European Federation of Neurological
Societies (EFNS) recommends a presence of
Thiamine deficiency in alcohol dependence occurs two of the following four signs as evidence of
because of poor absorption of thiamine from the Wernicke’s encephalopathy :[15]
GI tract, impaired thiamine storage and reduced 1. Dietary deficiency
thiamine phosphorylation in the brain, reducing 2. Oculomotor abnormality
the amount of active thiamine in the brain. 3. Mild memory impairment
4. Altered mental status
36 ©Psych Scene Pty Ltd 2018. All rights reserved.
PSYCH INSIGHTS
Treatment of acute (WE) [15] [16] MRI findings in WKS
• Thiamine 500 mg IV tds for 2-3 days and 250 • Mamillary body atrophy
mg daily for next 3-5 days
• Neuronal loss in the anterior principal and
• Thiamine 100 mg PO tds for rest of hospital mediodorsal nuclei of the thalamus and the
stay basal forebrain
• Multivitamins The most obvious neuroradiological sign of
• Replace lost Mg acute WE, regardless of etiology, is bilateral
• Replace fluid and electrolyte losses hyperintensity on late-echo MRI, generally
occurring in gray matter tissue of the mammillary
Clinicians suspecting Wernicke’s bodies, anterior and medial nuclei of the thalamus,
encephalopathy in a patient should treat periventricular gray matter, inferior and superior
it as an emergency and provide optimum colliculi. [17]
intravenous treatment in order to avoid
permanent brain damage. (BNF) Image from Case courtesy of Dr Lee-Anne Slater,
Radiopaedia.org. From the case rID: 12151
Prophylactic treatment for patients at risk of
WE – Thiamine 200-300mg IM daily for 3-5 days.
Korsakoff’s Syndrome Wernicke’s Encephalopathy -
High intensity signal around
Undiagnosed and untreated WE can lead to
Korsakoff’s syndrome in 80% of cases. periventricular areas.
Clinical features: 37
First described by Victor (1971)
An abnormal mental state in which memory
and learning are affected out of all proportion to
other cognitive functions in an otherwise alert
and responsive patient
• Anterograde amnesia (impaired ability to
acquire new episodic memories)
• Confabulation
• Retrograde amnesia
• Lack of insight
• Disorientation in time and place
• Executive dysfunction
• Sequelae of WE
Psych Scene Hub
Impact of Alcohol
NEUROPSYCHIATRIC COMORBIDITIES
Psychiatric disorders are commonly associated with alcoholism, and the compounded dysfunction of
their comorbidity is a critical element in the diagnosis and treatment of these patients.
There are four main hypotheses in dual diagnosis cases:
Neuropsychiatric comorbidities
A national survey (SAMHSA) in 2014 showed that of the 20 million American adults with a substance use
disorder, almost 8 million also suffered from a mental illness .[18]
Mood and anxiety disorders are common alcohol abuse disorders with one large epidemiological study
showing that over 30% of individuals with alcohol dependency had a co-morbid mood disorder .[19]
In this study, it was shown that alcohol dependency comes with a 4-times increase in the risk of
developing major depressive disorder.
Conversely, there are also high rates of alcohol-related disorders in psychiatric patients, particularly in
those with bipolar disorder and depression when compared to the general population ,[19] .[20]
Patients with schizophrenia are also highly likely to suffer from alcohol abuse due to their tendency to
devalue negative consequences and overvalue rewards .[21]
38 ©Psych Scene Pty Ltd 2018. All rights reserved.
PSYCH INSIGHTS
CONCLUSION
Excessive alcohol consumption is associated
with structural changes in certain brain areas
and functional changes to neurotransmitter
pathways that cause impairments to cognition and
behaviour. The effects, however, differ from person
to person.
Exciting developments are happening in the
world of addiction that will allow clinicians and
researchers to develop targeted therapies that
may be able to prevent addiction and alcohol-
related brain damage in dependent individuals.
39
Psych Scene Hub
The Simplified
Guide to the
Gut Brain Axis
How the Gut and The Brain Talk to Each Other
The gut-brain axis (GBA) is a bidirectional link between the central nervous system (CNS) and the
enteric nervous system (ENS) of the body. It involves direct and indirect pathways between cognitive
and emotional centres in the brain with peripheral intestinal functions. The GBA involves complex
crosstalk between the endocrine (hypothalamic-pituitary-adrenal axis), immune (cytokine and
chemokines) and the autonomic nervous system (ANS).
The GBA primarily combines the sympathetic and parasympathetic arms of the autonomic nervous
system (ANS), which drives both afferent and efferent neural signals between the gut and the brain,
respectively. The HPA axis meanwhile coordinates adaptive responses against stress including
activation of memory and emotional centres in the limbic system of the brain.
The neuro-immuno-endocrine mediators of the GBA allow the brain to influence intestinal function
(immune cells, epithelial cells, enteric neurons, and smooth muscle cells). Moreover, the cells of
the gastrointestinal (GI) tract are also under the influence of the gut microbiota and recent evidence
suggests that there is an emerging concept whereby the microbiome plays an important role in the
GBA structure [1].
40 ©Psych Scene Pty Ltd 2018. All rights reserved.
THE MICROBIOME PSYCH INSIGHTS
The microbiome refers to all microorganisms in or 41
on their host as well as their genetic material. The
microbiota, on the other hand, defines the microbe
population in a specific ecosystem, such as those
populations found in the gut microbiota or skin
microbiota.
Within the gut, there are approximately 1014
microorganisms, which is around 10 fold
more cells than there are human cells in the
human body. Collectively, the genetic material
of the microbiome is approximately 150 times
greater than the human genome, which has led
some scientists to label the microbiome as a
‘superorganism’.
In recognition of this superorganism and the
mutualistic co-evolution of humans and microbes,
the Human Microbiome Project was set up to
analyse this unique relationship to determine its
role in health and disease. This is particularly
important given the rise in modern antimicrobial
treatments, disinfectant use and harsh cleaning
products that are frequently marketed and sold as
necessary for good human health.
Within the gut, the bacterial species
Firmicutes and Bacteroides are
approximately 75% of the gut microbiota
and both of these species are very
sensitive to change [2].
Disruptions to the microbiome are increasingly
becoming associated with the prevalence of
allergies, autoimmune diseases, metabolic
disorders and neuropsychiatric disorders that
affect today’s society.
Psych Scene Hub
Gut Brain Axis
THE GUT BRAIN LINK
A newborn is first exposed to the mother’s vaginal microbiota which influences the offsprings microbial
signature. Studies show that the gut microbiota is central to the development and maturation of the
human CNS and ENS in these early postnatal weeks [3]. The interaction between the GI mucosal lining
and the gut microbiome also helps to fine tune the developing immune system.
Much of the research into the brain-gut-microbiota axis has involved germ-free animals and studying
the effect of antibiotics, probiotics and fecal transplants to determine their effects of the gut microbiota
on brain activity. Many of these studies suggest that the gut microbiota produces relevant levels of
neurotransmitters and are, in part, responsible for many facets of health and disease.
The microbes of the gut microbiota interact with the GBA through the following pathways.
1. The Vagus nerve – Afferent Spinal and vagal 5. Altered Intestinal Permeability – Chronic
sensory neurons carry feedback from the stress has been shown to alter intestinal
intestinal end to the brain stem which inturn permeability (leaky gut syndrome), which is
engages the hypothalamus and limbic system associated with a low-grade inflammation
(responsible for regulation of emotions). that can be functionally linked to psychiatric
Similarly, descending projections from the disorders such as depression [4]. In many of
limbic system (activated via stress) influence these cases, it is the increased presence
autonomic activity of the gut. of circulating bacterial endotoxins, known
as lipopolysaccharides (LPS), which are
2. Neuroendocrine (gut hormone) signalling fundamental risk factors for disease.
– Bacterial products are known to stimulate Alternatively, other studies have suggested that
enteroendocrine cells (EECs) to produce the gut microbiota can produce neuroactive
several neuropeptides such as peptide substances that may influence the core
YY, neuropeptide Y (NPY), cholecystokinin, symptoms of neuropsychiatric disorders4. This
glucagon-like peptide-1 and -2, and substance alternative hypothesis could signify a critical
P These neuropeptides then enter the and relevant role of gut microbiota in the
bloodstream and/or directly influence the pathophysiology of many disorders, including
enteric nervous system. schizophrenia, autism, anxiety and depression.
3. Interference with Tryptophan metabolism 6. Production of Microbial Metabolites
– Approximately 95% of Serotonin (5-HT) is – Many species of Lactobacillus and
produced by gut mucosal enterochromaffin Bifidobacterium produce gamma-aminobutyric
cells. Peripherally, 5-HT is involved in the acid (GABA), which is the main inhibitory
regulation of GI secretion, motility (smooth neurotransmitter in the brain. In addition,
muscle contraction and relaxation), and pain Candida, Escherichia, and Enterococcus
perception, whereas in the brain 5-HT is produce the neurotransmitter serotonin, while
implicated in regulating mood and cognition. some Bacillus species have been shown to
Gut microbiota also play an important role in produce dopamine. Bacteria also produce
tryptophan metabolism which is the precursor short-chain fatty acid (SCFAs), such as butyric
to the production of Serotonin. acid, propionic acid and acetic acid, that are
able to stimulate sympathetic nervous system,
4. The Immune System – The gut associated mucosal serotonin release and thus influence
lymphoid tissue comprises 70% of the body’s the memory and learning process in the brain.
immune system and can be conceptualised as
the largest immune organ in the body.
42 ©Psych Scene Pty Ltd 2018. All rights reserved.
PSYCH INSIGHTS
# !
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The Gut Microbiota interacts with the brain through
several mechanisms. These include interaction with
enteroendocrine cells resulting in the production
of neuropeptides (5 HT, CCK, PPY), activation of
immune cells to produce cytokines, production of
microbial metabolites and activation of vagus nerve
all of which can influence brain physiology impacting
neurotransmission, neurogenesis and neuroinflammation.
Stress, on the other hand, activates the limbic system
which can influence gut physiology through descending
nervous system projections which synapse on the gut
mucosa. This, in turn, can alter microbiome composition.
This intricate network thus exerts effects which alter both
GI and brain function.
43
Psych Scene Hub GUT BRAIN AXIS
AND MAJOR
Gut Brain Axis DEPRESSIVE
DISORDER
GUT MICROBIOTA
AND Much of the research into intestinal microbial
NEUROPSYCHIATRIC composition has been carried out using animal
DISORDERS models, either by adding pathogenic bacteria
and monitoring behaviour or by inducing
There is mounting interest in determining how depression-like symptoms and rescuing
the gut microbiota can influence and contribute these animals through treatment.
to the pathogenesis of neuropsychiatric
disorders. In a study by Desbonnet and colleagues, they
showed that rats that had undergone maternal
Research supports GI microbe-brain separation (model of induced depression-like
interactions most notably with anxiety and behaviour) could be rescued by treatment
depressive-like behaviours with accumulating with the probiotic Bifidobacterium infants in
evidence pointing to specific microbial genes conjunction with 30-mg/kg citalopram [8].
that can regulate neurotransmitter activity [5].
You can read the full nature article here. Maternal separation causes reduced mobility,
increased peripheral proinflammatory
In one study, Asano and colleagues showed interleukin (IL)-6 secretion, and reduced levels
that Clostridium produced biologically active of norepinephrine in these rats. However, these
dopamine in the gut lumen of mice [6]. Given symptoms were reversed after treatment with
that dopamine is the key neurotransmitter both the probiotic and citalopram but not when
associated with schizophrenia, it is possible that they were administered separately.
these bacterial metabolites can interact and
stimulate the central and peripheral nervous Functional MRI analysis has previously shown
systems. there is a chronic low-level inflammatory
condition in many cases of depression. In
In another study, there was a strong correlation these cases, depression is reliably associated
found between functional GI disorders caused with inflammatory biomarkers such as
by dysbiosis and the subsequent presence of tumour necrosis factor (TNF)- , IL-6, and
mood disorders [7]. C-reactive protein. There are several lines of
evidence that suggest that the presence of
Dysbiosis is a microbial disturbance or these inflammatory markers is suggestive of
imbalance that can cause functional GI gut permeability issues and the presence of
disorders such as inflammatory bowel disease inflammatory inducers such as LPS.
(IBD) and ulcerative colitis. Interestingly, it is
also well established that the response of the
CNS to psychological and physical stressors can
affect gut homoeostasis and result in diseases
such as ulcerative colitis and irritable bowel
syndrome (IBS).
44 ©Psych Scene Pty Ltd 2018. All rights reserved.
PSYCH INSIGHTS
GUT BRAIN AXIS AND AUTISM SPECTRUM
DISORDER (ASD)
Autism-spectrum disorder (ASD) is a group caused by ingestion of either antibiotics against
of neurodevelopmental disorders that are these bacteria or probiotics that provide the gut
characterised by deficits in social interactions with more synergistic bacteria.
including verbal and nonverbal behaviours.
Furthermore, analysis of faecal samples from
Researchers believe that these ASD-like ASD children has shown an imbalance in certain
behaviours are a result of a complex interplay microbiota species with overall less diverse
between genetic defects and environmental risk gut microbiota species [9]. It was reported that
factors causing abnormal neurodevelopment these compositional differences included a
during maturation in utero and in early childhood. lower abundance of Prevotella and Coprococcus
species. The differences in microbial diversity
Analysis of genetic material in faecal matter from and composition will result in changes in many
children with ASD showed a correlation between neuroactive microbial metabolites. Therefore,
bacteria such as Clostridium and Desulfovibrio GI dysbiosis is a possible factor in ASD
and altered neuro-behavioural development as etiopathogenesis just as it has been suggested to
observed in ASD [9]. Anecdotally, there have been be a causative factor in psychiatric disorders such
observations of improved symptoms in ASD as depression.
children who experience changes in gut microflora
populations caused by ingestion of either The differences in microbial diversity and
composition results in changes in many
Anecdotally, there have been observations neuroactive microbial metabolites. Therefore,
of improved symptoms in ASD children who GI dysbiosis is a possible factor in ASD
experience changes in gut microflora populations etiopathogenesis.
45
Psych Scene Hub
Gut Brain Axis
GUT BRAIN AXIS AND IRRITABLE BOWEL
SCHIZOPHRENIA SYNDROME
Many of the studies on gut microbiota and Irritable bowel syndrome (IBS) is a gastrointestinal
schizophrenia have been preclinical studies and disorder characterised by altered bowel habits
carried out in a schizophrenia-like behaviour rat in association with abdominal discomfort or
model. Experiments show that treatment with the pain in the absence of detectable structural and
human commensal bacteria, Bacteroides fragilis biochemical abnormalities.
can improve microbiota composition, correct gut
permeability, and improve anxiety-like symptoms Psychiatric co-morbidity e.g depression and
in this model .[10] anxiety are overrepresented in individuals with
IBS. Besides altered gastrointestinal motility,
Furthermore, clinical studies on subjects with visceral hypersensitivity, post-infectious reactivity,
schizophrenia showed the presence of increased alteration in faecal micro flora, bacterial
levels of lactic acid bacteria in the gut lumen, overgrowth, food sensitivity, carbohydrate
including Lactobacillus casei, and Lactobacillus malabsorption, and intestinal inflammation, the gut
lactis as well as Streptococci species such brain alteration is known to be a major factor in
as Streptococcus mutans and Streptococcus the pathogenesis of IBS .[12]
thermophilius .[11]
Modulation of the gut-brain axis in IBS offers a
The increased presence of these bacteria species promising therapeutic target for the future.
is associated with alterations in adaptive Th2
immune responses which is known to be present
in schizophrenia. Administration of probiotics
to these individuals altered the microbiome
and appeared to normalise some behavioural
symptoms.
In addition, the pathogenic bacteria Clostridium
is known to produce 3-(3-hydroxyphenyl)-3-
hydroxypropionic acid (HPHPA) and p-cresol,
which are microbial metabolites that can inhibit an
enzyme called dopamine beta-hydroxylase.
This enzyme converts dopamine to norepinephrine
causing a concurrent rise in dopamine levels in
the brain. This can lead to behavioural problems
and has been associated with exacerbating
psychotic episodes in schizophrenia.
46 ©Psych Scene Pty Ltd 2018. All rights reserved.
PSYCH INSIGHTS
MANIPULATING THE GUT MICROBIOTA
The gut microbiota can be intentionally manipulated to help maintain health and prevent or treat disease.
1. Probiotics 2. Antibiotics
Recent experimental evidence would appear to Antibiotics reduce the numbers and
suggest that alterations to the gut microbiota diversity of commensal bacteria, which can
composition through probiotic treatment could allow pathogenic or parasitic microbes an
attenuate neuropsychiatric symptoms or even opportunity to thrive in. Wholesale microbiota
reduce the risk of developing future psychiatric changes caused by antibiotics have been
symptoms. shown to influence adult behaviour through
modulation of hormone expression levels and
As an example, treatment with Lactobacillus tryptophan metabolic pathways, which are
rhamnosus induced region-dependent associated with serotonin secretion.
changes in GABA expression in the cortical
cingulate, hippocampus, amygdala and In a previous article on the Hub, the study we
prelimbic regions .[13] This treatment thereby covered showed that mice that were treated
reduced the stress-induced release of cortisol, with antibiotics performed worse on memory
which in turn reduced anxiety and depression- tests due to impairments in hippocampal
related behaviour. neurogenesis. However, if mice were given
probiotics or an exercise wheel, they showed
profound improvements. The researchers
showed that a specific subset of monocytes
act as a communicating cell between the
brain, the immune system, and the gut.
3. Diet and Lifestyle
Diet manipulation can influence gut
microbiota by affecting composition and
function of the microbial community. These
alterations, in turn, can modulate the innate
and adaptive immune systems as well as
influence behaviour and mood.
A recent study showed that a gluten-free diet
improved schizophrenia symptoms in a single
case where the individual also had a complex
autoimmune disorder .[14] Although remission
from psychotic symptoms was attributed to
the maintenance of a gluten-free diet, further
studies are needed to determine the impact of
dietary gluten in patients with schizophrenia
and who are also gluten-sensitive.
47
Psych Scene Hub
Gut Brain Axis
CONCLUSION
The mutualistic synergy between microbes and humans is a relationship that is
essential for growth, development, health and the prevention of disease.
“The past 5 years have seen an amazing increase in our knowledge of how bacteria
signal to the brain and the implications this has for psychiatry. There are still many
open questions, however.
Firstly, the mechanisms of how the microbiota signals to the brain are only slowly
being unraveled. We are at the very early stages of research, which will need to
employ experimental rigor that must be employed to unequivocally demonstrate that
it is the actual production of a neurochemical in vivo by a specific microorganism, and
not a non-neurochemical aspect of the microorganism, such as a cell wall component
interacting with immune cells in the gut, that is responsible for a specific change in
behavior.
Secondly, the individual components of bacteria that are mediating their effects need
to be disentangled. The evolving field of metabolomics is advancing and assisting in
our ability to better understand the signaling cascades and roles of bacterial products.
Thirdly, as most of the studies to date have been in rodents, further human studies are
needed to determine if bacteria-based interventions can indeed have a positive effect
on mental health, a so-called psychobiotic effect.
Although some preliminary studies have focused on the altered composition of the
microbiota in depression and autism, the time is now ripe for a comprehensive
analysis of the microbiota in other disorders, including schizophrenia, anxiety, drug
addiction, and eating disorders followed by mechanistic studies that will determine if
such changes have any causal relationship to psychiatric symptomatology [15].”
(Foster et al., 2016)
48 ©Psych Scene Pty Ltd 2018. All rights reserved.
PSYCH INSIGHTS
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